Short summary

The prevalence of celiac disease has increased fivefold since 1950. The gut microbiota in the first years of life is important for development of the immune system and thus possibly for development of immune mediated diseases as celiac disease. Mode of delivery, early infant feeding, and use of antibiotics are the most important determinants for the gut microbiota. We aim to study the association between these early determinants of gut microbiota and the risk of celiac disease.

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Rationale

Are changes in the gut microbiota in early life the cause of the increasing prevalence of celiac disease?

Pediatric disease has changed over the last century so that morbidity and mortality caused by infections are reduced while the incidence of immune mediated diseases such as celiac disease, type 1 diabetes, and allergies is increasing. Infectious diseases are reduced by improved hygiene and use of antibiotics. Improved hygiene and use of antibiotics has also led to changes in the gut microbiota.

The gut microbiota in early life plays an important role in development of the immune system. Therefore, an association is suggested between environmental exposures affecting the gut microbiota in the first years of life and immune mediated diseases such as celiac disease.

Establishment of the gut microbiota starts at birth. The most important environmental exposures for establishment of the gut microbiota are mode of delivery, infant feeding and use of antibiotics.

The objective is to study the association between the most important environmental exposures (mode of delivery, infant feeding and use of antibiotics) affecting the gut microbiota in the first years of life and the risk for later development of celiac disease.

We use two of the largest birth cohorts in the world: 'The Danish National Birth Cohort' and the 'Norwegian Mother and Child Cohort Study' with a total of 200,000 children and link the data to independent data from Danish and Norwegian national health registers.

The project will contribute significantly to the understanding of the pathogenesis of celiac disease. The prevalence of celiac disease differs considerably between Denmark and Norway and we may be able to suggest an explanation for this. If an association is confirmed, further research in this area may present an opportunity to prevent celiac disease by ensuring a beneficial microbiota early in life.

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Description of the cohort

We include all children born in Denmark in the period 1995 to 2012 corresponding to about 1,200,000 children with a total observation time of about 11,000,000 person years. Children diagnosed with celiac disease are identified in the Danish National Patient Register and the National Register of Pathology. The diagnosis is confirmed by combining information on hospital admissions in the Danish National Patient Register, histological descriptions of duodenal biopsies in the National Register of Pathology, and celiac disease specific antibodies and HLA-haplotypes registered in patient records. We expect to identify about 1000 children with confirmed celiac disease. Information on mode of delivery is registered in the Danish Medical Birth Register. Information on use of antibiotics is registered in the Danish Prescription Database. The Danish National Birth Cohort includes 100,000 children born in the period 1996-2003 corresponding to about 30 % of all births in this period. The children were followed since 12^th week of gestation and detailed information on environmental exposures and health has been collected included information on infant feeding.

We include all children born in Norway in the period 2004-2012 corresponding to about 540,000 children with a total observation time of about 2,000,000 person years. Children diagnosed with celiac disease are identified in the Norwegian National Patient Register. The diagnosis is confirmed by contact to the families. We expect to identify about 1000 children with confirmed celiac disease. Information on exposure variables are registered in Norwegian national registers corresponding to the Danish registers.

Data and biological material

We include Danish data from the Danish National Patient Register, the Danish Medical Birth Register, the Danish National Birth Cohort, the Danish Prescription Database, the National Register of Pathology, patient records, and Statistics Denmark.

We include Norwegian data from the Norwegian National Patient Register, the Medical Birth Register of Norway, the Norwegian Mother and Child Cohort Study, and the Norwegian Prescription Database.

Collaborating researchers and departments

HCA Research, Hans Christian Andersen Children's Hospital, Odense University Hospital, Professor Steffen Husby, MD, DMSci, Section of Social Medicine, Department of Public Health, University of Copenhagen

• Professor Anne Marie Nybo Andersen, MD, PhD

Department of Epidemiology, Norwegian Institute of Public Health

• Senior researcher Ketil Størdal, MD, PhD